Jan 13, 2016
The Menace of Hepatitis BThe Menace of Hepatitis B
By
Professor
Dr Intekhab AlamDepartment of MedicineKhyber Medical University, PGMI, LRH, Peshawar
What is Hepatitis B ?What is Hepatitis B ?
Hepatitis B is an infectious disease caused by Hepatitis B is an infectious disease caused by hepatitis B virus which may lead to cirrhosis, hepatitis B virus which may lead to cirrhosis, hepatic decompensation and HCC.hepatic decompensation and HCC.
Hepadnavirus family, DS DNA, Enveloped.Hepadnavirus family, DS DNA, Enveloped.
It is the 10It is the 10thth leading cause of death in the world leading cause of death in the world
HBV is 50 to 100 times more infectious than HIVHBV is 50 to 100 times more infectious than HIV
10% of HIV patients are co-infected with HBV10% of HIV patients are co-infected with HBV
Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. Journal of Viral Hepatitis, Volume 11, Number 2, March 2004, pp. 97-107
WHO Fact Sheet. 2000Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative (University of Wisconsin) (University of Wisconsin)
Hepatitis B virus (HBV)Hepatitis B virus (HBV)
HBV Genotypes and SubtypesHBV Genotypes and Subtypes
GenotypeGenotype Areas of prominenceAreas of prominence
AA NW Europe, USA, NW Europe, USA, Central AfricaCentral Africa
BB Taiwan, Japan, Indonesia, Taiwan, Japan, Indonesia, China, VietnamChina, Vietnam
CC E Asia, Taiwan, Korea, China, E Asia, Taiwan, Korea, China, Japan, VietnamJapan, Vietnam
DD Mediterranean area, IndiaMediterranean area, India
EE W AfricaW Africa
FF Central and S AmericaCentral and S America
G & HG & H France, USAFrance, USA
Stuyver et al 2000
The Global Impact of HBV DiseaseThe Global Impact of HBV Disease
World population
6 billion
2 billion with evidence of
HBV infection
300–400 million with
chronic HBV
25% die of cirrhosis or liver cancer
Global Patterns of Chronic HBV Global Patterns of Chronic HBV InfectionInfection
High(High(>>8%): 45% of global population8%): 45% of global population– Lifetime risk of infection >60% Lifetime risk of infection >60% – Early childhood infections commonEarly childhood infections common
Intermediate(2%-7%): 43% of global populationIntermediate(2%-7%): 43% of global population– Lifetime risk of infection 20%-60%Lifetime risk of infection 20%-60%– Infections occur in all age groupsInfections occur in all age groups
Low (<2%): 12% of global populationLow (<2%): 12% of global population– Lifetime risk of infection <20% Lifetime risk of infection <20% – Most infections occur in adult risk groupsMost infections occur in adult risk groups
Hepatitis B – In AsiaHepatitis B – In Asia
Of all chronically infected carriers worldwide, Of all chronically infected carriers worldwide, approximately 75% are found in Asia.approximately 75% are found in Asia.
In Pakistan In Pakistan (Intermediate prevalence area):(Intermediate prevalence area): – 5% of the population is affected by hepatitis B5% of the population is affected by hepatitis B– 67% of HCC cases are a result of HBV. 67% of HCC cases are a result of HBV.
R Mohamed et al. Practical difficulties in the management of hepatitis B in the Asia–Pacific region. Journal of Gastroenterology and Hepatology (2004) 19, 958–969
HBV vs HIV
HIVHIV HBVHBVNo. of people infected worldwide No. of people infected worldwide (WHO estimated)(WHO estimated)
19.5 million19.5 million 2000 million2000 million
No. of AIDS cases/HBV carriersNo. of AIDS cases/HBV carriers 6 million6 million 350 million350 million
Min. vol of blood required to Min. vol of blood required to transmit infectiontransmit infection
0.1 ml0.1 ml 0.0004 ml0.0004 ml
Risk of infection following needle-Risk of infection following needle-stick injury with positive patientstick injury with positive patient
0.5%0.5% 7-30%7-30%
Vaccine preventableVaccine preventable NoNo YesYes
Transmission of HBVTransmission of HBV
HBV is ubiquitous, highly contagious and is 100 times HBV is ubiquitous, highly contagious and is 100 times more infectious than HIV.more infectious than HIV.
Transmission isTransmission is “Sexual, Parenteral, Perinatal”. “Sexual, Parenteral, Perinatal”.
Source of infection is unknown in one third of the Source of infection is unknown in one third of the patients.patients.
HBV can survive outside the body for prolonged periods.HBV can survive outside the body for prolonged periods.
Concentration of Hepatitis B VirusConcentration of Hepatitis B Virus in Various Body Fluids in Various Body Fluids
High Moderate Undetectable High Moderate Undetectable
Blood Blood semen semen urine urine
Serum Serum vaginal fluid vaginal fluid feces feces
Wound exudates Wound exudates saliva saliva sweat sweat
tearstears
breast milkbreast milk
Transmission of HBVTransmission of HBV
Host Recipient
Horizontal transmission Vertical transmission
Mother
Infant
Contaminated needlesSexual
Health care workerTransfusion
6% infected after age 5 years become chronically infected
90% infected infants become chronically infected
Perinatal
Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative Keefe MD. Pocket Guide to Hepatitis B A CME accredited program developed by members of the ACT-HBV Initiative (University of Wisconsin) . (University of Wisconsin) . CDC Fact Sheet. 2005CDC Fact Sheet. 2005
Spectrum of DiseaseSpectrum of Disease
Acute HBV
infection
Chronic HBV
infection
Fatal progressive liver failure
Cirrhosis HCC
DeathDecompensated
cirrhosis
Fulminant hepatic failure
15–40%*
~1%
90–95% neonatal infection
50% childhood infection
5–10% adult infection
*Lok et al 2002
Ac. clinical illness (jaundice) <5 yrs: <10% Ac. clinical illness (jaundice) <5 yrs: <10% >5 yrs: 30-50%>5 yrs: 30-50%
Aetiology and Disease Characteristics of HBVAetiology and Disease Characteristics of HBV SummarySummary
HBV is a complex virus characterised by high HBV is a complex virus characterised by high infectivityinfectivity
Acute HBV infection usually resolves without medical Acute HBV infection usually resolves without medical interventionintervention
Chronic infection leads to increased risk of Chronic infection leads to increased risk of progressive liver disease, cirrhosis and deathprogressive liver disease, cirrhosis and death
Chronic infection is the target of therapeutic Chronic infection is the target of therapeutic interventionintervention
HBeAg-negative variant is associated with a more HBeAg-negative variant is associated with a more aggressive form of the diseaseaggressive form of the disease
Early intervention prevents development to HBeAg-Early intervention prevents development to HBeAg-negative diseasenegative disease
Importance of DiagnosisImportance of Diagnosis
Early diagnosis is important to prevent progression Early diagnosis is important to prevent progression and transmission, and helps to:and transmission, and helps to:
– confirm HBV infectionconfirm HBV infection– assess stage and grade of diseaseassess stage and grade of disease– monitor disease progressionmonitor disease progression
Require monitoring…• Inactive disease may not remain inactive• Liver damage may occur if HBV reactivates
Require treatment
40%60%
HBV is a dynamic disease!!!
Patients may develop the need for treatment later
The importance of monitoringThe importance of monitoring
Signs and symptoms of acute HBV AVHSigns and symptoms of acute HBV AVH
They are the same for all types of hepatitis from A to E They are the same for all types of hepatitis from A to E i.e: malaise, arthralgias, anorexia, fever, headache, dark i.e: malaise, arthralgias, anorexia, fever, headache, dark colored urine, yellow discoloration of sclerae and pain or colored urine, yellow discoloration of sclerae and pain or discomfort in RHC.discomfort in RHC.
Extraheptic findings more common in HBV AVH.Extraheptic findings more common in HBV AVH.– Arthralgia, skin rash (papular dermatitis), polyarterits Arthralgia, skin rash (papular dermatitis), polyarterits
nodosa, glomerulonephritis……..etcnodosa, glomerulonephritis……..etc
Acute infectionAcute infection– High ALTHigh ALT
– HBsAgHBsAg
– IgM Anti HBcIgM Anti HBc(following parameters are present but need not be tested)(following parameters are present but need not be tested)
– HBeAgHBeAg
– Elevated HBV DNAElevated HBV DNA
Resolving Resolving InfectionInfection– HBsAg seroconversionHBsAg seroconversion
– HBeAg seroconversionHBeAg seroconversion
– IgG Anti-HBcIgG Anti-HBc
Acute HBV MarkersAcute HBV Markers
Chronic HBV MarkersChronic HBV Markers
Chronic infection Chronic infection – HBsAg measured 6 months apartHBsAg measured 6 months apart
– Absence of IgM anti-HBcAbsence of IgM anti-HBc
– HBeAg +iveHBeAg +ive
– HBV DNA +iveHBV DNA +ive
– Raised, fluctuating ALTRaised, fluctuating ALT
Immuneescape
< <> >HBeAg+ve HBeAg–ve
ALT
HBV-DNA
Inactive (carrier) state
HBeAg –ve active chronic hepatitis
HBeAg +ve chronic hepatitis
Immune tolerance
Immuneclearance
Immunecontrol
Characteristic phases of CHB infectionCharacteristic phases of CHB infection
Outcome of HBV infection is determined by the strength of Outcome of HBV infection is determined by the strength of the immune responsethe immune response
– complex interplay between the host immune response and complex interplay between the host immune response and
– replication status of the virusreplication status of the virus
95% of adults spontaneously clear virus95% of adults spontaneously clear virus
However, 90% of newborns will develop chronic infectionHowever, 90% of newborns will develop chronic infection– 25% lifetime risk of end-stage liver disease or liver cancer25% lifetime risk of end-stage liver disease or liver cancer
The natural history of hepatitis B:The natural history of hepatitis B:the importance of immune controlthe importance of immune control
Importance of anti HBcAb detectionImportance of anti HBcAb detection(occult HBV infection)(occult HBV infection)
Anti HBc positive but HBsAg and HBsAb Anti HBc positive but HBsAg and HBsAb negative???:negative???:
- - CHB with BDL of HBsAg & DNA:CHB with BDL of HBsAg & DNA: commonly seen in commonly seen in individuals with HIV and HCV co infection.individuals with HIV and HCV co infection.
- - marker of immunity after acute infection:marker of immunity after acute infection: with BDL with BDL HBsAb, respond well to a single shot of HBV vaccine.HBsAb, respond well to a single shot of HBV vaccine.
- - False positive:False positive: especially in people from low prevalence especially in people from low prevalence areas respond well to routine vaccination.areas respond well to routine vaccination.
- - TThe only marker in the window period of HBV AVH.he only marker in the window period of HBV AVH.
Holistic approach to CHBHolistic approach to CHB ““CHB is a lifelong infection”.CHB is a lifelong infection”.
Identification of those at risk of liver disease.Identification of those at risk of liver disease.
Education (lifelong monitoring, reactivation)Education (lifelong monitoring, reactivation)
Vaccination (all household and sexual contacts)Vaccination (all household and sexual contacts)
Judicious introduction of antiviral therapyJudicious introduction of antiviral therapy
Appropriate screening for HCC.Appropriate screening for HCC.
Counseling after HBsAg detectionCounseling after HBsAg detectionFamily screening and vaccination.Family screening and vaccination.
Barrier protection (safe sex) for spouse till active immunity Barrier protection (safe sex) for spouse till active immunity has developed in the spouse following vaccination.has developed in the spouse following vaccination.
Arrange HBIG and vaccine for the newborn in HBsAg +ive Arrange HBIG and vaccine for the newborn in HBsAg +ive mothers diagnosed during pregnancy.mothers diagnosed during pregnancy.
Regarding performing exposure prone procedures by Regarding performing exposure prone procedures by HCWs ???HCWs ???
Risk of blood transfusion and non-hepatic and hepatic Risk of blood transfusion and non-hepatic and hepatic transplant donation.transplant donation.
Sharing of tooth brushes and razors.Sharing of tooth brushes and razors.
Cover open cuts and scratches.Cover open cuts and scratches.
Should receive 2 doses of HAV vaccine 6-18 months apart.Should receive 2 doses of HAV vaccine 6-18 months apart.
Don’t…………..Don’t…………..Impose any dietary restriction.Impose any dietary restriction.
Restrict physical activities.Restrict physical activities.
Isolate them in schools and daycare centers.Isolate them in schools and daycare centers.
Separate their utensils.Separate their utensils.
Stop marital relations.Stop marital relations.
Stop them from kissing their near and dear ones.Stop them from kissing their near and dear ones.
Clinical terms used in HBV infectionClinical terms used in HBV infectionChronic Hepatitis B (CHB):Chronic Hepatitis B (CHB): can be further subdevided intocan be further subdevided intoHBeAg Positive HBeAg Positive disease( Harbouring Wild type HBV) or HBeAg negative disease (Seen in those with longer disease( Harbouring Wild type HBV) or HBeAg negative disease (Seen in those with longer infection with precore/ core HBV variant).infection with precore/ core HBV variant).
Inactive HBsAg carrier state:Inactive HBsAg carrier state: HBsAg +ive, anti HBc +ive with normal rest of the HBsAg +ive, anti HBc +ive with normal rest of the markers.markers.
Resolved Hepatitis B:Resolved Hepatitis B: a known HBV AVH patient who has cleared HBsAg and has a known HBV AVH patient who has cleared HBsAg and has developed Anti HBs Antibodies.developed Anti HBs Antibodies.
Acute Exacerbation or flare of hepatitis B:Acute Exacerbation or flare of hepatitis B: intermittent elevation of ALT to 10X intermittent elevation of ALT to 10X ULN or 2X the baseline value.ULN or 2X the baseline value.
Reactivation of Hepatitis B:Reactivation of Hepatitis B: Reappearance of active necroinflammatory disease in a Reappearance of active necroinflammatory disease in a known inactive carrier.known inactive carrier.
HBeAg seroconversionHBeAg seroconversion:: appearance of anti HBe Ab with loss of HBeAg. appearance of anti HBe Ab with loss of HBeAg.
HBeAg clearance:HBeAg clearance: loss of HBeAg without appearance of HBeAb. loss of HBeAg without appearance of HBeAb.
HBeAg reversion:HBeAg reversion: reappearance of HBeAg in a patient who was known to have reappearance of HBeAg in a patient who was known to have seroconvertedseroconverted
Inactive CarriersInactive Carriers(previously Healthy stable carriers)(previously Healthy stable carriers)
Persons who have HBsAg and Anti HBc IgG positive for > 6 months Persons who have HBsAg and Anti HBc IgG positive for > 6 months with normal ALT, HBeAg –ive, HBeAb +ive, serum DNA levels with normal ALT, HBeAg –ive, HBeAb +ive, serum DNA levels <2,000 IU/ml (in up to 67-80% pts) and normal liver histology.<2,000 IU/ml (in up to 67-80% pts) and normal liver histology.
4-20% carriers may revert back to HBeAg positivity. ~30% of them 4-20% carriers may revert back to HBeAg positivity. ~30% of them have raised ALT with high HBV DNA levels.have raised ALT with high HBV DNA levels.
10-20% of carriers may reactivate and develop serious sequelae 10-20% of carriers may reactivate and develop serious sequelae from chronic hepatitis B in their lifetimefrom chronic hepatitis B in their lifetime
Spontaneous HBsAg clearance rate is 0.5% per year.Spontaneous HBsAg clearance rate is 0.5% per year.
Take home message:Take home message:
•Lok and McMahon. AASLD guidelines on chronic hepatitis B. Hepatology vol. 34, no. 6, 2001
Follow up with serial testing is mandatory to confirm maintenance of inactive carrier stateFollow up with serial testing is mandatory to confirm maintenance of inactive carrier state
Immuneescape
< <> >HBeAg+ve HBeAg–ve
ALT
HBV-DNA
Inactive (carrier) state
HBeAg –ve active chronic hepatitis
HBeAg +ve chronic hepatitis
Immune tolerance
Immuneclearance
Immunecontrol
treat treatmonitor monitor
Who should be considered for treatment?Who should be considered for treatment?
Role of liver biopsyRole of liver biopsy
It is important to note that liver histology improves It is important to note that liver histology improves significantly in patients with sustained response to significantly in patients with sustained response to treatment or spontaneous seroconversion to HBeAb.treatment or spontaneous seroconversion to HBeAb.
Liver histology is most useful in patients who do not Liver histology is most useful in patients who do not meet clear cut guidelines for treatment e.g; if ALT is meet clear cut guidelines for treatment e.g; if ALT is 1-2 ULN with +ive HBeAG and DNA levels of > 20000 1-2 ULN with +ive HBeAG and DNA levels of > 20000 IU/mlIU/ml
Revised upper limit of ALT should be 30U/l for men and Revised upper limit of ALT should be 30U/l for men and 19U/l for women.19U/l for women.
Decision to do liver biopsy should take into consideration Decision to do liver biopsy should take into consideration the age, new suggested ULN for ALT, HBeAg status, the age, new suggested ULN for ALT, HBeAg status, HBV DNA levels and other clinical features suggestive of HBV DNA levels and other clinical features suggestive of CLD.CLD.
Time to abandon liver biopsy?Time to abandon liver biopsy?
Major issues:Major issues: cost, patient acceptability and anxiety, cost, patient acceptability and anxiety, invasive nature of the procedure, inherent complications, invasive nature of the procedure, inherent complications, 80% accurate in staging liver fibrosis, must be 25mm 80% accurate in staging liver fibrosis, must be 25mm long piece to avoid sampling error long piece to avoid sampling error (only 20% liver biopsies (only 20% liver biopsies fulfill this criteria).fulfill this criteria).
Alternatives:Alternatives:
– Serum biomarkers: Serum biomarkers: 80-85% specific, better at extreme of stages80-85% specific, better at extreme of stages
– Fibroscans/Stiffness scans/Elastographs:Fibroscans/Stiffness scans/Elastographs: 95% specific. 95% specific.
Aims of Therapy for Chronic HBV InfectionAims of Therapy for Chronic HBV InfectionShort-term goals of treatment dependent on HBeAg statusShort-term goals of treatment dependent on HBeAg status– HBeAg-positive: sustained* ‘e’ seroconversion/HBV DNA HBeAg-positive: sustained* ‘e’ seroconversion/HBV DNA
suppression/ALT normalisationsuppression/ALT normalisation
– HBeAg-negative: sustained* HBV DNA suppression/ALT HBeAg-negative: sustained* HBV DNA suppression/ALT normalisationnormalisation
Ultimate goalUltimate goal– HBsAg SeroconversionHBsAg Seroconversion
Overall goalOverall goal– prevent/stop/reduce liver damage and progression to cirrhosis prevent/stop/reduce liver damage and progression to cirrhosis
and/or HCCand/or HCC– prolong survivalprolong survival
“ “HBV never ‘cured’ but controlled”HBV never ‘cured’ but controlled”Though the sharks are circling but the lifeboats are outThough the sharks are circling but the lifeboats are out
*treatment response maintained beyond end-of-treatment during a follow-up period of 6 months or more
Anti-HBV therapy and HBV DNA suppressionAnti-HBV therapy and HBV DNA suppression
Balance between viral replication and host immune Balance between viral replication and host immune responseresponse
Aim is to reduce viral replication in order to facilitate Aim is to reduce viral replication in order to facilitate sustained host-mediated immune control of virussustained host-mediated immune control of virus
Antiviral activity alone is not always sufficient to achieve Antiviral activity alone is not always sufficient to achieve this aimthis aim– Particularly in patients with relatively inactive immune responses Particularly in patients with relatively inactive immune responses
(e.g.. low or normal ALT levels) (e.g.. low or normal ALT levels)
Treatment strategiesTreatment strategies
Initiate and maintain remissionInitiate and maintain remission
Sustain suppressionSustain suppression
Prevent reactivationPrevent reactivation
Prevent progression to liver failure/HCCPrevent progression to liver failure/HCC
Timely treatment which is safe and cost effective. Timely treatment which is safe and cost effective.
Factors associated with progression of HBV Factors associated with progression of HBV related liver disease.related liver disease.
Host and viral risk factors Host and viral risk factors for cirrhosisfor cirrhosis
Old ageOld age
HBV genotype C.HBV genotype C.
High levels of HBV DNA.High levels of HBV DNA.
Alcohol consumption.Alcohol consumption.
Co infection with: Co infection with: HCV HCV HDV or HIV.HDV or HIV.
Smoking.Smoking.
Host and viral risk factors Host and viral risk factors for HCCfor HCC
Male gender.Male gender.
Family H/O HCC.Family H/O HCC.
Older age.Older age.
H/O HBeAg reversion.H/O HBeAg reversion.
Presence of cirrhosis.Presence of cirrhosis.
HBV genotype C.HBV genotype C.
Core promotor mutation.Core promotor mutation.
Co infection with HCV.Co infection with HCV.
ALTALT HBV DNAHBV DNA
≤≤2 x ULN2 x ULN <100,000 <100,000 cp/mLcp/mL
20,000 IU/mL20,000 IU/mL
Observe, consider treatment when ALT becomes Observe, consider treatment when ALT becomes elevatedelevated1,2,31,2,3
Consider liver biopsy if ALT 1–2 x ULN or Consider liver biopsy if ALT 1–2 x ULN or intermittently elevated, age >40yrsintermittently elevated, age >40yrs11, family history , family history HCCHCC11
If moderate/severe inflammation or advanced fibrosis→ If moderate/severe inflammation or advanced fibrosis→ treatmenttreatment11
>2 x ULN>2 x ULN >100,000 >100,000 cp/mLcp/mL
20,000 IU/mL20,000 IU/mL
Observe for 3–6 months, treat if no spontaneous Observe for 3–6 months, treat if no spontaneous HBeAg seroconversionHBeAg seroconversion1,2,31,2,3
Immediate treatment if overt hepatic Immediate treatment if overt hepatic decompensationdecompensation1,31,3
1. Lok and McMahon Hepatology 2007 (AASLD Guidelines) 2. EASL Consensus Statement J Hepatol 2003 (EASL Guidelines)3. Liaw et al Liver International 2005 (Updated APASL Guidelines)
Treatment recommendations for Treatment recommendations for HBeAg-positive patientsHBeAg-positive patients
Treatments and molecules approved or licensed or Treatments and molecules approved or licensed or in late-stage development for CHBin late-stage development for CHB
Interferon-αLamivudine
Adefovir
Telbivudine
PEG-IFNα-(2a)EntecavirApproved 2005/6: Approved 2005/6:
Approved pre-2005:Approved pre-2005:
Clevudine(approved in Korea)
ApprovedApproved
Phase II/III–ongoing:Phase II/III–ongoing: Pradefovir
Active against HBV and Active against HBV and approved for HIV:approved for HIV:
Tenofovir
Emtricitabine
In developmentIn development
Subcutaneous
Less potent DNA suppression
Antiviral and immunomodulatory
Frequent side effects
No resistance
HBsAg seroconversion more common
Finite duration of therapy
Direct antivirals Interferon-based
Oral administration
Potent HBV DNA suppression
No immunomodulatory effects
Few side effects
Risk of resistance
HBsAg seroconversion rare
Indefinite Rx – drug fatigue
Pros and cons of each approach?Pros and cons of each approach?
The primary aim of antiviral therapy with The primary aim of antiviral therapy with nucleos(t)ide analogues…nucleos(t)ide analogues…
……is suppression of HBV DNA below the level associated with diseaseis suppression of HBV DNA below the level associated with disease
The primary aim of interferon-based therapy…The primary aim of interferon-based therapy…
……is is to allow host-mediated immune control of the virusto allow host-mediated immune control of the virus
Direct antivirals Interferon-based
Patient/physician preferenceConsider risk of drug resistance
Length of treatmentSide effects
Immunocompetent
Compensated liver disease
Younger patients
Immunosuppressed
Advanced liver disease
IFN/PEG-IFN non-responders
High ALT
Low HBV DNA
Liver histology
Who should be treated with what?Who should be treated with what?
HBe Ag loss or seroconversion.HBe Ag loss or seroconversion.
HBsAg loss/seroconversionHBsAg loss/seroconversionConstitutes the outcome closest to a ‘cure’ of CHB in clinical practiceConstitutes the outcome closest to a ‘cure’ of CHB in clinical practice
HBV DNA suppressionHBV DNA suppression– Usually follows HBeAg seroconversionUsually follows HBeAg seroconversion– Relevant in the context of nucleos(t)ide analogues – Relevant in the context of nucleos(t)ide analogues –
to prevent resistance developmentto prevent resistance development
ALT normalisation.ALT normalisation.
Improved histology.Improved histology.
What are the most relevant markers of What are the most relevant markers of therapeutic success in HBeAg-positive CHB?therapeutic success in HBeAg-positive CHB?
HBeAg seroconversion (%)
HBV DNA loss* (%)
HBsAg loss (%)
*Hybridisation or bDNA assays for LAM, PCR for ADV and ETV¥HBeAg loss, not seroconversion
EASL consensus statement. J Hepatol 2003 Lok and McMahon. 2004;
Dienstag et al. N Engl J Med 1999;Lau et al. N Eng J Med 2005;
Marcellin et al. N Engl J Med 2003; Chang et al. N Engl J Med 2006;
Lai et al. AASLD 2005
Histology (%)
PLB
23–25
16
4–6
–
LAM
49–56
44
16–19
≤ 1
ADV
53
21
12
0
ETV
72
67
21
2
LdT
70
60
26¥
–
On-therapy response to approved On-therapy response to approved NAs at 1 year in HBeAg-positive CHBNAs at 1 year in HBeAg-positive CHB
1. Chang T-T, et al. NEJM 2006; 354:1000–1010. 2. Marcellin P, et al. NEJM 2003; 1. Chang T-T, et al. NEJM 2006; 354:1000–1010. 2. Marcellin P, et al. NEJM 2003; 348(9):808348(9):808––816 816 33. Lau G, et al. NEJM 2005; 352:2682–2695 . Lau G, et al. NEJM 2005; 352:2682–2695
Comparison of treatments at 1 year in Comparison of treatments at 1 year in antiviral-naïve HBeAg(+) patients*antiviral-naïve HBeAg(+) patients*
Peg IFN Peg IFN [3][3]
Lamivudine Lamivudine [1][1]
Adefovir Adefovir [2][2]
Entecavir Entecavir [1][1]
% HBV DNA % HBV DNA UndetectableUndetectable
2121
3636
2525
6767
00
2020
4040
6060
8080% HBeAg % HBeAg
SeroconversionSeroconversion
27272121
12121818
00
2020
4040
6060
8080
**Collation of currently available data – not from head-to-head studiesCollation of currently available data – not from head-to-head studies
LLOQLLOQ Assay Assay LLOQLLOQ Assay Assay (copies/mL)(copies/mL) (copies/mL) (copies/mL)ETVETV 300300 Cobas Amplicor HBV PCR Cobas Amplicor HBV PCR ADVADV 400400 Amplicor HBV DNA PCRAmplicor HBV DNA PCRLVDLVD 300300 Cobas Amplicor HBV PCR Cobas Amplicor HBV PCR Peg IFNPeg IFN 400400 Cobas Amplicor HBV PCRCobas Amplicor HBV PCR
HBeAg seroconversion: Comparison of treatments HBeAg seroconversion: Comparison of treatments at 1 year in nucleoside-naïve HBeAg(+) patients*at 1 year in nucleoside-naïve HBeAg(+) patients*
*Collation of currently available data – not from head-to-head studies
27
21
12
18
22
0
10
20
30
40
HB
eAg
ser
oco
nve
rsio
n
(% p
atie
nts
)
Peg IFN
Lamivudine
Adefovir
Telbivudine
Entecavir
Lai CL, et al. Hepatology 2005; 42:748A (AASLD abstract LB01).Lai CL, et al. Hepatology 2005; 42:748A (AASLD abstract LB01).Lau G, et al. NEJM 2005; 352:2882–2695. Lau G, et al. NEJM 2005; 352:2882–2695. Chang T-T, et al. NEJM 2006; 354:1000–1010.Chang T-T, et al. NEJM 2006; 354:1000–1010.Marcellin P, et al. NEJM 2003;Marcellin P, et al. NEJM 2003;348:808348:808––816.816.
HBeAg seroconversion: Comparison of HBeAg seroconversion: Comparison of treatments at 2 years in nucleoside-naïve treatments at 2 years in nucleoside-naïve
HBeAg(+) patients*HBeAg(+) patients*
**At 72 weeks (6 months post-treatment follow-up); **At 72 weeks (6 months post-treatment follow-up); ††Through last observation (on- and 6-months off-treatment)Through last observation (on- and 6-months off-treatment)
Lau G, et al. NEJM 2005; 352: 2682–2695.Lau G, et al. NEJM 2005; 352: 2682–2695.Gish R, et al. Hepatology 2005; 42 (Suppl 1) 267A–268A (abstract 181). Gish R, et al. Hepatology 2005; 42 (Suppl 1) 267A–268A (abstract 181). Marcellin P, et al. J Hepatol 2005; 42:31–32 (Abstract 73).Marcellin P, et al. J Hepatol 2005; 42:31–32 (Abstract 73).Lai C-L, al. Hepatology 2006; 44 (Suppl. 1): 222A (abstract 91). Lai C-L, al. Hepatology 2006; 44 (Suppl. 1): 222A (abstract 91).
*Collation of currently available data – not from head-to-head studies
0
20
40
60
80
HB
eAg
ser
oco
nve
rsio
n
(% p
atie
nts
)
303126
2932
Peg IFN**
Lamivudine†
Adefovir
Telbivudine
Entecavir†
Population Population DurationDuration HBeAg loss/seroconversion rates*HBeAg loss/seroconversion rates*
OverallOverall1–81–8 12–52 weeks12–52 weeks 1212––44% 44% (2–12 months f/u)(2–12 months f/u)
CaucasiansCaucasians1–41–4 12–52 weeks12–52 weeks 1919––44% 44% (2–12 months f/u)(2–12 months f/u)
AsiansAsians4–84–8 12–24 weeks12–24 weeks 1212––28% 28% (6–12 months f/u)(6–12 months f/u)
1. Di Bisceglie et al. Am J Gastroenterol 1993; 2. Fattovich et al. J Hepatol 1989;3. Yalcin et al. Clin Infect Dis 2003; 4. Thomas et al. J Viral Hepat 1994;
5. Cooksley et al. J Viral Hepat 2003; 6. Lok et al. Lancet 1988; 7. Lok et al. Gastroenterology 1992; 8. Yuen et al. Hepatology 2001
* Intent-to-treat analyses
Off-therapy HBeAg response with Off-therapy HBeAg response with conventional IFNconventional IFN for HBeAg-positive CHB for HBeAg-positive CHB
0
10
20
30
40
32%
19%
Pat
ien
ts (
%)
PEGASYS+ placebo
PEGASYS+ lamivudine
Lamivudine
27%
87/271 74/271 52/271
p = NS p = 0.023
p < 0.001
Lau et al. N Engl J Med 2005
PEGASYS:PEGASYS: HBeAg seroconversion HBeAg seroconversion 24 weeks post-treatment24 weeks post-treatment
PEGASYSPEGASYS
+ placebo+ placebo
(n=271)(n=271)
PEGASYSPEGASYS
+ LAM+ LAM
(n=271)(n=271)
LamivudineLamivudine
(n=271)(n=271)
HBeAg-positive CHB n HBeAg-positive CHB n (%)(%) 8 (3%)8 (3%) 8 (3%)8 (3%) 0 (0%)0 (0%)
p = 0.004*
p = 0.004*
Lau et al. N Engl J Med 2005* Fisher’s Exact Test
Sustained HBSustained HBssAg seroconversion: Ag seroconversion: 24 weeks post-treatment24 weeks post-treatment
59/69 14/103
Lau et al. EASL 2006, oral
• 172 patients from the PEGASYS monotherapy arm entered the long-term study: 69 responders and 103 non responders
0
10
20
30
4039%
Pa
tient
s (%
)
69/172
50
48 weekspost-treatment
42%
73/172
24 weekspost-treatment
HBeAg seroconversion HBeAg seroconversion Long-term roll-over study: 1-year analysisLong-term roll-over study: 1-year analysis
86%
14%
Response to therapy – naïve patientsResponse to therapy – naïve patients
Long-term resultsLong-term results
Lamivudine maintenance therapy can slow disease progression – but is compromised by resistance development
0
5
10
15
20
25
% o
f p
atie
nts
Years1 2 3
Less disease progression in lamivudine-treated patients vs placebo However, response compromised by development of resistance
1 2 3 1 2 3
Years Years
Disease progression Increased Child-Pugh score HCC
Placebo (n=215) Lamivudine (n=436)
Liaw et al. N Engl J Med 2004
Wild-type (n=221)YMDD mutants (n=209) (49%)
Time after randomisation (months)
0
5
10
15
20
25
0 6 12 18 24 30 36
Time to disease progression according to LAM-resistant YMDD mutant status
Pa
tient
s w
ith d
ise
ase
pro
gre
ssio
n (
%)
Placebo (n=215)
5%
13%
21%
Liaw et al. N Engl J Med 2004
Years
39%
0%
54%
3%
57%
29%
18%11%
Pa
tient
s w
ith r
esis
tanc
e (
%) 63%
0
10
20
30
40
50
60
70
1 2 3 4 5
NA
Lok et al. Gastroenterology 2003; Hadziyannis et al. N Engl J Med 2005; Tassopoulos et al. Hepatology 1999; Santantonio et al. J Hepatol 2000; Rizzetto et al. J Hepatol 2003; Locarnini et al. EASL 2005; Colonno et al. AASLD
2004; Lampertico et al. EASL 2004; Hadziyannis et al. AASLD 2005; Zoulim, ISVHLD 2006; Gish et al. J Hepatol 2005; Lai et al. Gastroenterology 2005; Standring EASL 2006
LAM ADV ETV LdT
0%5%
0% NA
Resistance development increases over timeResistance development increases over time
6%*
*LAM-R
HostHostPoor compliancePoor compliance
Inadequate doseInadequate dose
High BMIHigh BMI
High ALTHigh ALT
CirrhosisCirrhosis
VirusVirusHBeAg-positiveHBeAg-positive
High HBV DNAHigh HBV DNA
Failed initial virological Failed initial virological responseresponse
Pre-existing mutationsPre-existing mutations
Drug resistance: risk factorsDrug resistance: risk factors
To slow development of resistance to NAs, To slow development of resistance to NAs, combination therapy appears to be preferential to combination therapy appears to be preferential to sequential therapysequential therapy
Need trials of oral combination therapy before we can Need trials of oral combination therapy before we can advocate dual therapyadvocate dual therapy
– Need to include risk of drug resistance in Need to include risk of drug resistance in cost analysiscost analysis
Is there a role for combination therapy Is there a role for combination therapy using NAs?using NAs?
84
Proportion of patients surviving Proportion of patients free of hepatic complications
Months Months
1.0
0.8
0.6
0.4
0.2
24 36 48 60 72 8412 24 36 48 60 7212
IFN-treated WITH HBeAg clearance
1.0
0.8
0.6
0.4
0.2
IFN-treated WITHOUT HBeAg clearance
P=0.004* P=0.018*
* According to the proportional hazards model Niederau et al. N Eng J Med 1996
HBeAg seroconversion with IFNHBeAg seroconversion with IFN therapy is therapy is associated with improved survivalassociated with improved survival
Cu
mu
lativ
e %
HB
sAg
loss 50
40
30
20
10
01047852260
IFN
LAM
Weeks of follow-upvan Nunen et al. Gut 2003; van Zonneveld et al. Hepatology 2004; Lau et al. NEJM 2005;
Janssen et al. Lancet 2005; Lok and McMahon. 2004;Dienstag et al. NEJM 1999; Marcellin et al. NEJM 2003; Chang et al. NEJM 2006
Rates of HBsAg loss
Immune based therapy 24 weeks post-treatment• PEG-IFN 3–7% Direct antiviral therapies one year on-treatment • Adefovir 0%• Lamivudine ≤1%• Entecavir 2%
IFNs or NAs..? IFNs or NAs..? HBsAg loss after HBeAg seroconversionHBsAg loss after HBeAg seroconversion
IFNIFN-treated-treatedpatientspatients(n=233)(n=233)
Matched untreated Matched untreated controlscontrols(n=233)(n=233)
CirrhosisCirrhosis 18%18%p p = 0.041*= 0.041*
34%34%
HCCHCC 3%3%p p = 0.011*= 0.011*
13%13%
SurvivalSurvival 98%98%p p = 0.003*= 0.003*
53%53%
Lin et al. EASL 2005 and J Hepatol 2007*p vs control
Follow-up: mean 11 years (median 6.6 years; range: 1.1 to 16.5 years)
Long-term outcome of IFNLong-term outcome of IFN treatment in treatment inHBeAg-positive CHB: 11-year follow-upHBeAg-positive CHB: 11-year follow-up
Response to therapyResponse to therapy
Pre-treated and/or resistant patients Pre-treated and/or resistant patients
Pa
tie
nts
(%
)
HBeAg loss HBeAg seroconversion
32%37%
26/71* 21/65†
PEGASYS treatment of patients previously treated with LAM and/or ADV(median treatment duration 49 weeks)
0
10
20
30
40
50
*7 patients (10%) had no assessment while on-treatment †6 patients had no available anti-HBe status at baseline and 9 patients (14%) had no assessment while on-treatment Marcellin et al. EASL 2006
PEGASYS: On-treatment HBeAg loss/ PEGASYS: On-treatment HBeAg loss/ seroconversion in patients pre-treated seroconversion in patients pre-treated withwith NAs NAs
0
10
20
30
5043.7%
Pat
ien
ts (
%)
End of treatment
24 weeks post-treatment
31.2%
7/16 5/16
40
* HBV DNA <105 copies/mL
HBsAg seroconversion in
13% of patients
Shi et al. APASL 2007
PEGASYS: Response in PEGASYS: Response in patients with NA resistancepatients with NA resistance
12 weeks PEGASYS + LAM followed by 12 weeks of PEGASYS monotherapyHBeAg seroconversion and virological response*
Non-naïve patients – SummaryNon-naïve patients – Summary
Prior treatment with LAM, ADV or both is Prior treatment with LAM, ADV or both is notnot a barrier to a barrier to treatment with PEGASYStreatment with PEGASYS
Switching patients from LAM to PEGASYS is effective in Switching patients from LAM to PEGASYS is effective in HBeAg-positive CHBHBeAg-positive CHB– Approx 1/3 LAM-R patients lost HBeAg and developed anti-HBe Approx 1/3 LAM-R patients lost HBeAg and developed anti-HBe
antibodies antibodies Some achieved HBsAg seroconversionSome achieved HBsAg seroconversion
NAsNAsLong-term maintenance (years)Long-term maintenance (years)
Risk of resistance, cross-Risk of resistance, cross-resistance – monitor closelyresistance – monitor closely
Use in combination?Use in combination?
Prescribe responsiblyPrescribe responsibly
Optimizing response in HBeAg-positive CHB Optimizing response in HBeAg-positive CHB through immune controlthrough immune control
InterferonesInterferonesShort-term, finite duration Short-term, finite duration (24-48 wks)(24-48 wks)
Long-term benefit in ~1/3 ptsLong-term benefit in ~1/3 pts
HBsAg seroconversion achievableHBsAg seroconversion achievable
No resistanceNo resistance
Prior exposure to NAs not a barrier to Prior exposure to NAs not a barrier to treatmenttreatment
For patients who do not respond or for whom IFN contraindicatedwe need to know how to use NAs appropriately
!
Limitations of Current Limitations of Current Treatments for Chronic HBVTreatments for Chronic HBV
Conventional IFNConventional IFNModest efficacyModest efficacy
Inconvenient thrice-Inconvenient thrice-weekly injectionsweekly injections
LamivudineLamivudineModest efficacyModest efficacy
Continuous/ Continuous/ indefinite duration indefinite duration of therapyof therapy
Viral rebound on Viral rebound on treatment cessation treatment cessation
High relapse ratesHigh relapse rates
Drug resistant Drug resistant YMDD mutantsYMDD mutants
Adefovir• Modest efficacy• Continuous/
indefinite duration of therapy
• Viral rebound on treatment cessation
• Potential for drug resistant mutants
• Risk of renal toxicity
• No sustained response (off-therapy) data
HBeAg-positive HBeAg-negative/anti-HBe-positive
Natural history of HBV: Natural history of HBV: development of HBeAg-negative CHBdevelopment of HBeAg-negative CHB
Phasesof HBV infection
Replicative or immune tolerance
phase
HBeAg clearance
Low-replicative phase
HBV reactivation
Wild-type HBV
Variant HBVBrunetto et al. J Hepatol 1991
HBeAg-positive CHB
Cirrhosis
Decompensation
Death
HBeAg-negative CHB
EASL Consensus Guidelines. J Hepatol 2003;Lok and McMahon. Hepatology 2007 (AASLD Guidelines)
HCC
• Worst prognosis• Worst sustained
response to Rx
Long-term follow-up particularly important
Chronic HBV infection has serious Chronic HBV infection has serious long-term consequenceslong-term consequences
ALTALT HBV DNAHBV DNA
≤≤2 x ULN2 x ULN<100,000 <100,000
cp/mLcp/mL
20,000 IU/mL20,000 IU/mL
Normal ALT: no treatment, monitorNormal ALT: no treatment, monitor1,2,31,2,3
ALT 1–2 x ULN : consider biopsy, treat if ALT 1–2 x ULN : consider biopsy, treat if moderate/severe necroinflammation or fibrosismoderate/severe necroinflammation or fibrosis11
>2 x ULN>2 x ULN >100,000 >100,000 cp/mLcp/mL
20,000 IU/mL20,000 IU/mL
TreatmentTreatment1,2,31,2,3
1. Lok and McMahon Hepatology 2007 (AASLD Guidelines) 2. EASL Consensus Statement J Hepatol 2003 (EASL Guidelines)3. Liaw et al Liver International 2005 (Updated APASL Guidelines)
Treatment recommendations for Treatment recommendations for HBeAg-negative patientsHBeAg-negative patients
Durability of response after LAM therapy is limited, with relapse Durability of response after LAM therapy is limited, with relapse on treatment cessation, in patients with long-term undetectable on treatment cessation, in patients with long-term undetectable HBV DNAHBV DNA11
LAM resistance may develop during maintenance therapy, even LAM resistance may develop during maintenance therapy, even with undetectable HBV DNAwith undetectable HBV DNA22
Although ADV treatment has a lower potential for resistance Although ADV treatment has a lower potential for resistance development, virological breakthrough occurs soon after development, virological breakthrough occurs soon after treatment withdrawaltreatment withdrawal33
Long-term durability of response to ETV is, as yet, unprovenLong-term durability of response to ETV is, as yet, unproven1.Fung et al. J Virol Hepat 2004;
2. Di Marco et al. Antiviral Ther 2005; 3. Hadziyannis et al. N Eng J Med 2005
Treatment durability with NAs in Treatment durability with NAs in HBeAg-negative patients is limitedHBeAg-negative patients is limited
Nucleos(t)ide analoguesNucleos(t)ide analogues– Continuous therapy required to maintain responseContinuous therapy required to maintain response– Few/no side effectsFew/no side effects– Development of resistance likely Development of resistance likely – Accumulating costsAccumulating costs
Interferon-based therapyInterferon-based therapy– Provides durable, long-term benefits without the need for continuous Provides durable, long-term benefits without the need for continuous
medicationmedicationDual antiviral and immunomodulatory effectsDual antiviral and immunomodulatory effectsPotential for HBsAg clearance should not be dismissedPotential for HBsAg clearance should not be dismissed
– More side effects but well toleratedMore side effects but well tolerated– No resistance developmentNo resistance development– Cost effective over long termCost effective over long term
What is the optimal strategy for long-term response in What is the optimal strategy for long-term response in HBeAg-negative CHB?HBeAg-negative CHB?
Hepatitis D Virus (HDV)Hepatitis D Virus (HDV)
Defective, single stranded RNA, satellite Defective, single stranded RNA, satellite virus.virus.Mode of transmission: Parenteral. Mode of transmission: Parenteral. Coinfection with HBVCoinfection with HBV– severe acute diseasesevere acute disease– low risk of chronic infectionlow risk of chronic infection
SuperinfectionSuperinfection– usually develops chronic HDV infectionusually develops chronic HDV infection– high risk of severe chronic liver diseasehigh risk of severe chronic liver disease
Geographic Distribution of HDV Infection
Geographic Distribution of HDV Infection
HDV PrevalenceHigh
Intermediate
Low
Very Low
No Data
Taiwan
Pacific Islands
Repeat observationsRepeat observations– HBV DNA >~20,000HBV DNA >~20,000 IU/ml IU/ml (100,000 cp/mL)(100,000 cp/mL)– ALT ALT ≥ 2X ≥ 2X ULN.ULN.
± liver biopsy with evidence of progressive liver ± liver biopsy with evidence of progressive liver diseasedisease
ANDANDPost organ transplantPost organ transplantPre chemotherapy/immunosuppressive therapyPre chemotherapy/immunosuppressive therapy
Who should be treated?Who should be treated?
Treatment strategiesTreatment strategies
Initiate and maintain remission – Initiate and maintain remission –
indefinite treatment (NAs)indefinite treatment (NAs)
Induce sustained response (IFNs) – Induce sustained response (IFNs) –
finite treatmentfinite treatment
Which strategy?Which strategy?
Best patients for NAs:Best patients for NAs:
Patients with contraindications to IFNsPatients with contraindications to IFNs
Those who have not responded to Those who have not responded to IFN-based therapy IFN-based therapy
Decompensated diseaseDecompensated disease
Which strategy?Which strategy?
Best patients for Interferones:Best patients for Interferones:
Those preferring a finite course of therapyThose preferring a finite course of therapy
Younger patientsYounger patients
NA failure or resistantNA failure or resistant
Compensated diseaseCompensated disease
1st choice Aiming for sustained remission
Using a treatment of finite durationeg pegylated or conventional IFN
Sustainedremission
yes
no*
2nd choice Maintained remission
Using a treatment of potentially indefinite duration
eg nucleos(t)ide analogues
*or IFN contraindicated / not tolerated
Survival
The importance of immune control in CHB: The importance of immune control in CHB: durable response without resistance – durable response without resistance –
ConclusionConclusion
vaccinationvaccination
Composition:Composition: recombinant HBsAg recombinant HBsAg
Efficacy:Efficacy: 95% (range 80-100%) 95% (range 80-100%)
Duration of immunity:Duration of immunity: 15 years 15 years
Schedule:Schedule: 3 doses: 3 doses:– Standard: 0,1,6 months with no booster.Standard: 0,1,6 months with no booster.– Rapid: 0,1,2,months and a booster at 12 m. Rapid: 0,1,2,months and a booster at 12 m. – Accelerated: 0,7,21 days and booster at 12 m.Accelerated: 0,7,21 days and booster at 12 m.
Dose:Dose: 10 10μμg for children, 20g for children, 20μμg for adults and g for adults and
40 40 μμg for immunocompromised patients.g for immunocompromised patients.
Hepatitis B Vaccine: Interruption of ScheduleHepatitis B Vaccine: Interruption of Schedule
““In a three-dose schedule, increasing the In a three-dose schedule, increasing the interval between the first and second doses interval between the first and second doses of hepatitis B vaccine has little effect on of hepatitis B vaccine has little effect on immunogenicity or final antibody titer.” immunogenicity or final antibody titer.”
““The third dose confers optimal protection, The third dose confers optimal protection, acting as a booster dose. Longer intervals acting as a booster dose. Longer intervals between the last two doses (4-12 months) between the last two doses (4-12 months) result in higher final titers of anti-HBs.”result in higher final titers of anti-HBs.”
CDC & Prevention. MWR 1991;40 (RR-13):1-19.CDC & Prevention. MWR 1991;40 (RR-13):1-19.
DHS/PP
Questions?
Thank you!Thank you!